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The Journal of Immunology, 2001, 167: 6711-6715.
Copyright © 2001 by The American Association of Immunologists

Cutting Edge

Cutting Edge: Secondary Lymphoid Organs Are Essential for Maintaining the CD4, But Not CD8, Naive T Cell Pool1

Zhenhua Dai2 and Fadi G. Lakkis2

Sections of Nephrology and Immunobiology, Department of Internal Medicine, Yale University School of Medicine, New Haven, CT 06520


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
Despite declining thymic output with age, the peripheral naive T cell pool of an adult animal remains remarkably stable. Therefore, a central question in immunology is how the naive T cell pool is maintained. Here we show that the maintenance of the naive CD4, but not CD8, T cell population in the thymectomized adult mouse is dependent on the presence of secondary lymphoid tissues. This finding is explained by the inability of naive CD4 T cells to sustain normal levels of the survival molecule Bcl-2 or to undergo homeostatic proliferation in the absence of secondary lymphoid organs. Thus, naive CD4 T cells must traffic through secondary lymphoid organs to maintain a stable CD4 pool while naive CD8 T cells encounter their survival and proliferation signals outside the organized structures of secondary lymphoid tissues.


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
Immunocompetence of an adult animal is dependent on the maintenance of stable naive and memory T cell populations. The homeostasis of the mature naive T cell pool is mediated by the long-term survival of individual T cells and by their ability to undergo homeostatic proliferation rather than by regulating T cell output from the thymus (1, 2, 3, 4, 5, 6). The precise mechanisms responsible for the maintenance of the naive T cell pool are not well understood. Previous studies have provided evidence that the long-term survival and homeostatic proliferation of naive CD4 and CD8 T cells are dependent on low level stimulation of the TCR by self class I and class II MHC molecules, respectively (5, 7, 8, 9, 10, 11, 12). Cytokines such as IL-7 have also been shown to play a role in the survival and homeostatic proliferation of naive CD4 and CD8 T cells in mice (13, 14). However, it is not known where naive T cells receive the survival and proliferation signals necessary for their maintenance.

Mature naive T cells circulate constantly throughout secondary lymphoid organs (the spleen, lymph nodes, and mucosal lymphoid tissues) after exiting the thymus (1, 15, 16, 17). Although it is accepted that naive T cells encounter foreign Ags and are activated only within the context of secondary lymphoid organs (18, 19), it is not known whether naive T cells also receive the signals necessary for their long-term maintenance within these organs. Using a mouse model in which some or all secondary lymphoid organs are absent, we demonstrate here that secondary lymphoid tissues are critical for the maintenance of the naive CD4, but not CD8, T cell pool. Two mechanisms accounted for the dramatic contraction of the naive CD4 T cell population in mice that lack all secondary lymphoid organs: 1) compromised cell survival due to decreased Bcl-2 expression, and 2) failure to undergo homeostatic proliferation. In contrast, naive CD8 T cells maintained normal Bcl-2 expression and underwent homeostatic proliferation in the absence of secondary lymphoid organs. These findings underscore the differential requirements for the maintenance of peripheral, naive CD4 and CD8 T cells and suggest that these T cell subpopulations are regulated independently.


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Mice

C57BL/6 mice were purchased from The Jackson Laboratory (Bar Harbor, ME). The aly/+ and aly/aly mice (C57BL/6 background) were purchased from CLEA Japan (Osaka, Japan). All mice were maintained under specific pathogen-free conditions. Adult thymectomy and splenectomy were performed under general anesthesia as previously described (4, 19).

Flow cytometry

Lymph node cells, splenocytes, and blood leukocytes were stained with the following mAbs (all from BD PharMingen, San Diego, CA): PE- or FITC-conjugated anti-mouse CD4, PE- or FITC-conjugated anti-mouse CD8, biotin-conjugated anti-CD44 followed by streptavidin-PerCP, and FITC-conjugated hamster anti-mouse Bcl-2 (3F11; BD PharMingen). Appropriate isotype-matched Abs were used as negative controls. Stained cells were analyzed by multicolor flow cytometry using a FACSCalibur (BD Biosciences, Mountain View, CA) and CellQuest software (BD Biosciences).

Measurement of homeostatic proliferation

aly/+ splenocytes were enriched for T cells by nonadherence to nylon wool and the CD44low T cell subpopulation was purified by cell sorting using a FACSCalibur (BD Biosciences). CD44low T cells were resuspended in HBSS (1 x 107 cells/ml) and incubated for 10 min at 37°C with 5 µM of CFSE (Molecular Probes, Eugene, OR) followed by two washes in HBSS. A total of 5 x 106 CD44low T cells labeled with CFSE were then adoptively transferred into the various mouse hosts by i.v. injection. One or 2 wk later, recipient mice were sacrificed. Peripheral blood T cells were then stained with PE-CD4 or PE-CD8 (BD PharMingen) and analyzed using a FACSCalibur (BD Biosciences) for CFSE fluorescence intensity after gating on either the CD4 or CD8 populations.


   Results
Top
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
Contraction of the peripheral CD4, but not CD8, T cell pool in thymectomized mice that lack secondary lymphoid organs

To test whether secondary lymphoid organs are essential for maintaining the peripheral T cell pool, we measured the total numbers of CD4 and CD8 T lymphocytes in wild-type or aly/+ mice, which have normal secondary lymphoid organs (20); splenectomized aly/+ mice, which lack the spleen; alymphoplastic mice (aly/aly), which lack lymph nodes and Peyer’s patches (20); and splenectomized aly/aly mice which are devoid of secondary lymphoid tissues. To exclude thymic contribution to the peripheral T cell pool, analyses were performed in mice 10 wk after adult thymectomy. Age-matched mice that did not undergo thymectomy were used as controls. Ten weeks after thymectomy, total CD4 and CD8 T cell numbers in the blood, lymph nodes, and the spleen of wild-type and aly/+ mice were lower than those in age-matched unthymectomized mice (Fig. 1Go), suggesting that the thymus plays a role in maintaining a fully replete peripheral T cell pool in the adult mouse. This finding is consistent with previous studies (21, 22, 23, 24). Removal of the spleen from thymectomized aly/+ mice did not alter the number of CD4 and CD8 T cells in the blood and lymph nodes (Fig. 1Go), suggesting that the spleen alone is not crucial for maintaining the peripheral T cell pool. In contrast, the number of CD4, but not CD8, T cells in the blood of thymectomized mice that lack lymph nodes and Peyer’s patches (aly/aly), or lack all secondary lymphoid organs (aly/aly-spleen), was significantly lower than that in the blood of thymectomized mice with normal secondary lymphoid tissues (C57BL/6 and aly/+) (Fig. 1Go). Similarly, the number of CD4, but not CD8, T cells was significantly reduced in the spleens of thymectomized aly/aly mice (Fig. 1Go).



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  		FIGURE 1. Secondary lymphoid organs are required for maintaining the peripheral CD4, but not CD8, T cell pool in adult thymectomized mice. The total number of mature CD4 and CD8 T cells in the blood, lymph nodes, and/or spleen was enumerated by flow analysis in the following groups (n = 5–6 mice per group): wild-type (C57BL/6) and aly/+ mice which have normal secondary lymphoid organs, splenectomized aly/+ mice (aly/+-spleen) which lack the spleen, alymphoplastic mice (aly/aly) which lack lymph nodes and Peyer’s patches (20 ), and splenectomized aly/aly mice (aly/aly-spleen) which are devoid of secondary lymphoid tissues. Mice were either left with an intact thymus and were analyzed at 14–16 wk of age (A), or they underwent adult thymectomy at age 4–6 wk and were analyzed 10 wk later (B). NA, not applicable; *, p < 0.05 compared with thymectomized aly/+ mice.

 
The reduced number of CD4 T cells in aly/aly and splenectomized aly/aly mice could not be attributed to sequestration of these cells in nonlymphoid tissues as histological and flow analyses did not reveal T cell infiltration of the liver and lungs (data not shown). This is consistent with the recent demonstration that naive T cells do not enter nonlymphoid tissues in the absence of inflammation (25). Moreover, migration of CD4 T cells to the bone marrow was not observed in splenectomized aly/aly mice (<0.4% of all cells in the bone marrow were CD4+ or CD8+ in either control aly/+ or in splenectomized aly/aly mice at 10 wk after thymectomy), suggesting that these cells do not migrate to the bone marrow in the absence of secondary lymphoid organs. Finally, surgical stress did not account for the decline in CD4 T cells in splenectomized aly/aly mice as aly/+ mice that underwent splenectomy had comparable CD4 T cell numbers to those observed in unsplenectomized aly/+ mice (Fig. 1Go). Therefore, the data indicate that the long-term maintenance of mature CD4 T cells in the periphery of an adult mouse is dependent on the presence of secondary lymphoid organs. In contrast, the maintenance of the peripheral CD8 T cell pool is independent of these organs.

Contraction of the peripheral CD4 T cell pool in the absence of secondary lymphoid organs is due to loss of naive (CD44low) T cells

The mature T cell pool consists of both naive and Ag-experienced lymphocytes. To determine which T cell subpopulation declines in the absence of secondary lymphoid organs, we measured the number of CD44low (naive) and CD44high (Ag-experienced) T cells in all mouse groups 10 wk after adult thymectomy. Age-matched unthymectomized mice were used as controls. In the absence of the thymus, the number of circulating CD4+CD44low T cells fell dramatically in mice that lack lymph nodes and Peyer’s patches (aly/aly) and in those that lack all secondary lymphoid organs (aly/aly-spleen) (8- and 17-fold lower than thymectomized aly/+ mice, respectively) (Fig. 2Go). In contrast, the decline in the number of circulating CD4+CD44high T cells was much more modest in thymectomized aly/aly and aly/aly-spleen mice (1.9- and 2.6-fold lower than thymectomized aly/+ mice, respectively) (Fig. 2Go). These findings indicate that the reduction in the number of peripheral CD4 T cells in the absence of secondary lymphoid organs is largely due to the contraction of the naive CD4 subpopulation.



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  		FIGURE 2. Maintenance of naive CD4, but not naive CD8, T cells is dependent on secondary lymphoid organs in adult thymectomized mice. The number of CD44low (naive) and CD44high (Ag-experienced) CD4 and CD8 T cells in the blood were enumerated by flow analysis in the same mouse groups described in Fig. 1Go in the presence (A) or absence (B) of the thymus. *, p < 0.05 compared with thymectomized aly/+ mice.

 
Reduced expression of Bcl-2 in naive CD4, but not CD8, T cells in the absence of secondary lymphoid organs

One mechanism by which the naive T cell pool is maintained is the long-term survival of individual T cells (1, 3). Because Bcl-2 is an anti-apoptotic protein that is critical for the survival of naive T cells (26), we examined whether the reduced number of naive CD4 T cells in the absence of secondary lymphoid organs is caused by an intrinsic survival defect such as decreased Bcl-2 expression. Circulating T cells from aly/+, aly/+-spleen, aly/aly, and aly/aly-spleen mice were analyzed for intracellular Bcl-2 expression 1 and 5 wk after thymectomy. At 1 wk after thymectomy, no significant difference in Bcl-2 expression in either CD8 or CD4 T cells was observed among the different mouse groups (Fig. 3Go). However, by 5 wk after thymectomy, Bcl-2 levels had declined significantly in CD4 T cells harvested from mice that lack lymph nodes and Peyer’s patches (aly/aly) and had declined further if the mice lacked all secondary lymphoid organs (aly/aly-spleen) (Fig. 3Go). In contrast, CD8 T cells maintained normal Bcl-2 levels in the absence of secondary lymphoid organs (Fig. 3Go). These findings suggest that CD4, but not CD8, T cells receive the signals necessary for sustaining Bcl-2 expression and thus, their long-term survival, within secondary lymphoid organs.



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  		FIGURE 3. Reduced Bcl-2 expression in CD4, but not CD8, T cells in the absence of secondary lymphoid organs. One and 5 wk after thymectomy, Bcl-2 expression was analyzed by flow analysis in peripheral blood CD4 and CD8 T cells of aly/+ mice (green histogram), aly/+-spleen mice (red histogram), alymphoplastic mice (aly/aly) (blue histogram), and aly/aly-spleen mice (orange histogram). A total of three experiments were performed.

 
Failure of naive CD4, but not CD8, T cells to undergo homeostatic proliferation in the absence of secondary lymphoid organs

Self-renewal (proliferation) is another mechanism by which the peripheral T cell pool is maintained (1, 3). Proliferation of naive T cells can be best demonstrated in a lymphopenic host, a phenomenon referred to as homeostatic proliferation (6, 27, 28). Therefore, we tested whether secondary lymphoid organs are necessary for the homeostatic proliferation of naive CD4 and CD8 T cells in mice rendered lymphopenic by adult thymectomy. CD44low T cells were isolated from aly/+ mice by cell sorting, labeled with the fluorescent dye CFSE, and then transferred into thymectomized mice that either have or do not have secondary lymphoid organs. One week later, recipient mice were sacrificed and analyzed for the proliferation of the transferred CD4 and CD8 T cell subpopulations. As shown in Fig. 4Go, adoptively transferred naive T cells did not proliferate in lymphocyte-replete mice (no thymectomy). In contrast, both CD4 and CD8 naive T cells proliferated vigorously in lymphopenic (thymectomized) hosts that have normal secondary lymphoid organs (aly/+) or lack the spleen only (aly/+-spleen) (Fig. 4Go). Naive CD8 T cells also proliferated adequately in thymectomized mice that lack lymph nodes and Peyer’s patches (aly/aly) or lack all secondary lymphoid organs (aly/aly-spleen) (Fig. 4Go), indicating that the homeostatic proliferation of naive CD8 T lymphocytes is independent of secondary lymphoid tissues. In sharp contrast, naive CD4 T cells failed to proliferate in thymectomized mice that lack all secondary lymphoid organs and exhibited minimal proliferation in those that lack lymph nodes and Peyer’s patches but have a spleen (Fig. 4Go). Homeostatic proliferation of CD4 T cells was not observed in splenectomized aly/aly mice even when CFSE-labeled lymphocytes were analyzed two weeks after adoptive transfer. These findings demonstrate that secondary lymphoid organs are crucial for the self-renewal of the naive CD4, but not CD8, T cell pool.



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  		FIGURE 4. Homeostatic proliferation of naive CD4, but not CD8, T cells in adult thymectomized mice is dependent on secondary lymphoid organs. aly/+ splenocytes were enriched for T cells by nonadherence to nylon wool and the CD44low subpopulation was purified by cell sorting. A total of 5 x 106 CD44low T cells labeled with the fluorescent dye CFSE were adoptively transferred into four groups of 14- to 16-wk-old mice that were either unthymectomized (No thymectomy) or thymectomized (Thymectomy) 10 wk earlier. Mice were sacrificed 7 days later and blood leukocytes were stained with PE-labeled anti-CD4 or anti-CD8. CFSE fluorescence intensity is shown after gating the CD4 and CD8 populations individually. A total of three experiments were performed.

 

   Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
It is accepted that naive T cells encounter foreign Ags and are activated only within the context of secondary lymphoid organs (18, 19). We demonstrated in this study that secondary lymphoid organs have another crucial role in the immune system, namely the maintenance of the mature naive CD4 T cell pool as naive CD4 T cells could not sustain normal levels of the survival molecule Bcl-2 or undergo homeostatic proliferation in the absence of secondary lymphoid organs. In contrast, we found that the survival and homeostatic proliferation of mature, naive CD8 T cells is independent of secondary lymphoid organs.

One explanation why peripheral CD4 T cell maintenance is dependent on secondary lymphoid organs is that naive CD4 T cells must interact with peptide:self-MHC class II molecules to survive and undergo homeostatic proliferation (7, 8, 9, 10, 12). However, recent studies have suggested that TCR-MHC class II interactions are not critical for the homeostasis of naive CD4 T cells (29, 30). Dorfman et al. (29) found that the survival of adoptively transferred naive CD4 T lymphocytes is not impaired in MHC class II-deficient hosts despite evidence for TCR signaling in these cells. Similarly, Clarke et al. (30) demonstrated that the long-term survival of naive CD4 T cells is only modestly affected by the absence of MHC class II molecules and that homeostatic proliferation is not absolutely dependent on the recognition of peptide:self MHC class II complexes. Therefore, it is possible that naive CD4 T cells receive MHC-independent survival and proliferation signals within the organized structures of secondary lymphoid organs.

Alymphoplasia in aly/aly mice is caused by a recessive mutation in the gene encoding NF-{kappa}B-inducing kinase (NIK)3 (31). However, this mutation does not account for the defective maintenance of naive CD4 T cells as the transfer of aly/aly bone marrow into wild-type mice leads to normal T cell reconstitution (32). Furthermore, naive aly/+ CD4 T cells, which have normal NIK activity, fail to proliferate when transferred to thymectomized aly/aly-spleen mice (Fig. 3Go), confirming that the maintenance of the naive CD4 T cell pool is dependent on secondary lymphoid organs and not NIK activity.

In contrast to CD4 T cells, we found that the long-term maintenance of the peripheral naive CD8 T cell population is independent of secondary lymphoid organs as naive CD8 T lymphocytes maintain a normal level of Bcl-2 and are capable of undergoing homeostatic proliferation in the absence of secondary lymphoid tissues. A possible explanation for this observation is that IL-7, produced in nonlymphoid tissues, sustains the survival and homeostatic proliferation of naive CD8, but not CD4, T cells in vivo (13, 14). Unlike our finding, Dummer et al. (33) found that both naive CD4 and CD8 T cells fail to proliferate in irradiated lymphotoxin {alpha} gene-knockout mice which lack discreet T cell zones in the spleen and lymph nodes. It is possible that the factors that regulate homeostatic proliferation in severely lymphopenic irradiated mice are different from those that regulate homeostatic proliferation in thymectomized mice which are mildly lymphopenic. Alternatively, the effects of irradiation on nonlymphoid tissues may hinder the homeostatic proliferation of naive CD8 T cells.

We also observed in this study that the persistence of Ag-experienced (CD44high) CD4 and CD8 T cells is largely independent of secondary lymphoid organs. This finding is consistent with the disparate homing patterns of naive and effector/memory T cells (34) and suggests that memory T cells may be sustained outside secondary lymphoid organs (35).


   Acknowledgments
 
We thank Maylene Wagener and Bogumila Konieczny (Emory University, Atlanta, GA) for assisting with adult thymectomy and splenectomy. We thank R. Ahmed (Emory University Vaccine Center), K. Murali-Krishna (University of Washington, Seattle, WA), and C. A. Janeway, Jr. (Yale University, New Haven, CT) for their helpful comments.


   Footnotes
 
1 This work was supported by National Institutes of Health Grants AI41643, AI44644, and AI49466. Back

2 Address correspondence and reprint requests to Dr. Fadi G. Lakkis or Dr. Zhenhua Dai, 333 Cedar Street, LMP 2073, P.O. Box 208029, New Haven, CT 06520. E-mail addresses: fadi.lakkis@yale.edu or zhenhua.dai{at}yale.edu Back

3 Abbreviation used in this paper: NIK, NF-{kappa}B-inducing kinase. Back

Received for publication September 26, 2001. Accepted for publication October 18, 2001.


   References
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 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

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